Hypertension-associated changes in neurohumoral control of arteries are well known but little is known about neurohumoral control of veins or how venous function is altered in hypertension. These studies will focus on mechanisms by which sympathetic nerves and endothelin-1 (ET-1) interact to contract veins and how this interaction is altered in the deoxycorticosterone acetate (DOCA)-salt model of hypertension in rats. Parallel studies will be done in arteries. DOCA-salt rats will be used as there are increases in ET- 1, sympathetic activity and venomotor tone in this hypertension model, Specific Aim 1 will test the hypothesis that transmitter release from sympathetic nerves in DOCA rats is increased due to impaired alpha2-adrenergic autoreceptor function. Disruption of alpha2 receptor function is caused by superoxide anions (O2-) produced by smooth muscle in response to ET-A receptor stimulation in DOCA rats. Neurogenic contractions of mesenteric arteries and veins will be studied in vitro and transmitter release from these tissues will be measured using HPLC. Studies in Specific Aim 2 will test the hypothesis that ET-B receptors are localized to sympathetic nerve terminals associated with mesenteric arteries and veins and activation of ET-A receptors facilitates transmitter release. Neurogenic contractions ofmesenteric arteries and veins will be studied in vitro and transmitter release will be measured using HPLC techniques. Irnmunohistochemical methods will be used to localize ET receptors in mesenteric arteries and veins. Studies in Specific Aim 3 will test the hypothesis that there is increased nerve-mediated depolarization and constriction of mesenteric veins in DOCA-salt rats in situ. Acute and chronic drug treatment protocols will be used to determine ifactions of ET- 1 on ET-A and ET-B receptors and/or O2- generation are responsible for augmented sympathetic venoconstriction during the development of DOCA-salt hypertension.. The focus on veins is highly novel and it is anticipated that these studies will provide new information about the etiology of salt-sensitive hypertension.